High yield and rapid synthesis methods for producing metallo-organic salts

ABSTRACT

A new method for preparing salts of metal cations and organic acids, especially divalent salts of alkaline earth metal ions from group II of the periodic system and carboxylic acids. The method comprising the use of a high temperature (about 90° or more) and, optionally. high pressure, in order to obtain a higher yield, purity and faster reaction speed than obtained with known synthesis methods. In particular, the present invention relates to the production of strontium salts of carboxylic acids. Novel strontium salts are also provided by the present method.

FIELD OF THE INVENTION

The present invention relates to methods of producing salts of metalcations and organic acids, especially salts of alkaline earth metal ionsfrom group II of the periodic system and carboxylic acids. Inparticular, the present invention relates to the production of strontiumsalts of carboxylic acids. New procedures and conditions for performingsuch synthesis with higher purity, higher yields and with shorterprocessing times, than has previously been possible are described in theinvention. Novel strontium salts are also provided by the presentmethod.

BACKGROUND OF THE INVENTION

Alkaline earth metals and alkali metals are almost invariably found inan oxidized state as a component of metallo-organic salts due to thehighly reactive nature of such elements. Salts of such metal-ions arewidely distributed throughout nature. The distribution and relativeabundance of various metal ions varies greatly, from very commonelements such as calcium, magnesium, potassium and sodium to less commonelements such as strontium, barium, lanthanum and gallium and very rareelements such as rubidium, caesium and beryllium.

Salts of alkaline earth metal and alkali metal compounds are used in agreat number of industrial processes and in production of food products,medical products, pharmaceutical ingredients, vitamins and other healthrelated products, products for personal care, as well as for a number ofindustrial products such as fertilizers, building materials, glass, ironand steel manufacture and in a great number of other products. Thus,efficient manufacture of pure metallo-organic salts is of enormouscommercial interest.

For many of the practical uses of alkaline earth metals, specific saltsmust be manufactured, which possess the properties required for thedesired application. Of particular interest for the present inventionare situations where the metal-ion salts must be manufactured with highpurity and with organic counter-ions not found in nature. Manufacture ofsuch salts is generally made by various aqueous processes and it is ingeneral difficult to control the homogeneity and purity of the reactionproducts necessitating re-crystallizations and other purification steps,which in turn results in low yields of the desired salt as appears fromBriggman B & Oskasson (1977), Schmidbaur H et al. (1989) and Schmidbauret al. (1990).

SUMMARY OF THE INVENTION

In one aspect, the invention relates to a method for the preparation ofan alkaline earth metal and/or another divalent metal ion salt of anorganic acid, the method comprising reacting at least one of a hydroxideand/or a halogen salt of the metal ion with the organic acid (anion) inan aqueous medium at a temperature of about 90° C. or more such as,e.g., about 100° C. or more, 120° C. or more, or about 125° C. or morefor a time period of at the most about 60 min such as, e.g. at the mostabout 30 min or at the most about 20 min such as about 15 min.

In one embodiment of this method, the salt is formed between an organicacid containing at least one carboxylic acid group and an alkaline earthmetal selected from the group comprising strontium, calcium andmagnesium.

In some embodiments of the method, the alkaline earth metal isstrontium. In some embodiments of the method, the organic acid is amono-, di-, tri- or tetra-carboxylic acid.

In some embodiments of the method, the organic acid is selected from thegroup comprising: acetic acid, C₂H₅COOH, C₃H₇COOH, C₄H₉COOH,(COOH)₂,CH₂(COOH)₂, C₂H₄(COOH)₂, C₃H₆(COOH)₂, C₄H₈ (COOH)₂, C₅H₁₀ (COOH)₂,fumaric acid, maleic acid, malonic acid, lactic acid, citric acid,tartaric acid, oxalic acid, ascorbic acid, benzoic acid, salicylic acid,phthalic acid, carbonic acid, formic acid, methanesulfonic acid,ethanesulfonic acid, camphoric acid, gluconic acid, L- and D-glutamicacid, pyruvic acid, L- and D-aspartic acid, trifluoroacetic acid,ranelic acid, 2,3,5,6-tetrabromobenzoic acid, 2,3,5,6-tetrachlorobenzoicacid, 2,3,6-tribromobenzoic acid, 2,3,6-trichlorobenzoic acid,2,4-dichlorobenzoic acid, 2,4-dihydroxybenzoic acid, 2,6-dinitrobenzoicacid, 3,4-dimethoxybenzoic acid, abietic acid, acetoacetic acid,acetonedicarboxylic acid, aconitic acid, acrylic acid, adipic acid,alpha-ketoglutaric acid, anthranilic acid, benzilic acid, arachidicacid, azelaic acid, behenic acid, benzenesulfonic acid,beta-hydroxybutyric acid, brassidic acid, capric acid, chloroacrylicacid, cinnamic acid, citraconic acid, crotonic acid,cyclopentane-1,2-dicarboxylic acid, cyclopentane carboxylic acid,cystathionine, decanoic acid, erucic acid, ethylenediaminetetraaceticacid, fulvic acid, fumaric acid, gallic acid, glutaconic acid, glutaricacid, gulonic acid, glucosamine sulphate, heptanoic acid, hexanoic acid,humic acid, hydroxystearic acid, isophthalic acid, itaconic acid,lanthionine, lauric acid (dodecanoic acid), levulinic acid, linoleicacid (cis, cis-9,12-octadecadienoic acid), malic acid, m-chlorobenzoicacid, melissic acid, mesaconic acid, methacrylic acid, monochloroaceticacid, myristic acid, (tetradecanoic acid), nonanoic acid, norvaline,octanoic acid, oleic acid (cis-9-octadecenoic acid), ornithine,oxaloacetic acid, palmitic acid (hexadecanoic acid), p-aminobenzoicacid, p-chlorobenzoic acid, petroselic acid, phenylacetic acid,p-hydroxybenzoic acid, pimelic acid, propiolic acid, propionic acid,p-tert-butylbenzoic acid, p-toluenesulfonic acid, pyruvic acid,sarcosine, sebacic acid, serine, sorbic acid, stearic acid (octadecanoicacid), suberic acid, succinic acid, terephthalic acid, tetrolic acid,threonine, L-threonate, thyronine, tricarballylic acid, trichloroaceticacid, trimellitic acid, trimesic acid, tyrosine, ulmic acid andcylohexane carboxylic acid.

In some embodiments of the method, the organic acid is an aminocarboxylic acid such as, e.g., a natural or synthetic amino acid. Forexample, n certain embodiments, the salt is selected from the groupconsisting of strontium glutamate, strontium aspartate, strontiummalonate, strontium D-glutamate, strontium L-glutamate, strontium (L-)diglutamate pentahydrate, strontium D-aspartate, strontium L-aspartate,strontium maleate, strontium ascorbate, strontium threonate, strontiumlactate, strontium pyruvate, strontium fumarate and strontium succinate.In specific embodiments, the salt is strontium malonate.

In some embodiments of the method, the molar ratio between the metal ionand the organic acid is in the range from 0.8:1 to 1.2:1, preferablyabove 1.05:1, such as above 1.1:1.

In specific embodiments of the method, the halogen salt is a chloridesalt.

In some embodiments of the method, the reaction is performed in a closedcontainer at a temperature of 100° C. or more and a pressure of 1 bar ormore.

In certain embodiments of the method, the yield of the divalent metalsalt is 70% or more such as, e.g., about 75% or more, about 80% or more,about 85% or more, about 90% or more or about 95% or more.

In some embodiments of the method, the amount of precipitated carbonateis less than 1%, such as less than 0.5% or less than 0.2% of the amountof divalent metal salt.

In some embodiments of the method, the method comprises, in addition toa divalent metal ion, a pharmaceutically active component containing anacid and/or amino group. In certain embodiments, the pharmaceuticallyactive component is selected from the group consisting of Non Steroidalanti inflammatory agents (NSAIDs), Cyclo-oxygenase-2 (COX-2) inhibitors,COX-3 inhibitors, inducible nitric oxide synthetase (iNOS) inhibitors,PAR2 receptor antagonists, neuroleptic agents, opioids, Cyclooxygenase(COX)-inhibiting nitric oxide donators (CINOD), Disease modifyinganti-rheumatic drugs (DMARD), bisphosphonates, N-acetylcholine receptoragonists, glycine antagonists, vanilloid receptor antagonists,neurokinin antagonists, N-Methyl-D-Aspartate (NMDA) receptorantagonists, calcitonin gene-related peptide antagonists and6-(5-carboxy methyl-hexyloxy)-2,2-dimethyl-hexanoic acid and analoguesthereof including active metabolites thereof.

In certain embodiments, the pharmaceutically active component is anNSAID selected from the group consisting of piroxicam, diclofenac,propionic acids including naproxen, flurbiprofen, fenoprofen, ketoprofenand ibuprofen, fenamates including mefenamic acid, paracetamol,indomethacin, sulindac, meloxicam, apazone, pyrazolones includingphenylbutazone, salicylates including aspirin.

In certain embodiments, the pharmaceutically active component isselected from the group comprising is an inhibitor of the cyclooxygenase2 enzyme (COX-2 inhibitor) with an inhibition constant below Ki 10 pmsuch as the following compounds: rofecoxib (Vioxx), valdecoxib (Bextra),celecoxib (Celebrex), etoricoxib (Arcoxia), lumiracoxib (Prexige),parecoxib (Dynastat), deracoxib (Deram), tiracoxib, meloxicam,nimesolide, (1,1-dimethylheptyl)-6 a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyrancarboxylic acid (CT-3); 2 (5H)-Furanone, 5,5-dimethyl(1-methylethoxy)[4(methylsulfonyl) phenyl]-(DFP); Carprofen (RIMADYLO);(Acetyloxy)-benzoic acid, 3-[(nitrooxy)-methyl]phenyl ester (NCX4016);P54 (CAS Reg. No. 1309960) 2,6-Bis(1,1-dimethylethyl)[(E)-(2-ethyl-1,1-dioxo isothiazolidinylidene)-methyl] phenol (S-2474);5(R)-Thio sulfonamide-3 (2H)-benzofuranone (SVT-2016) andN-[3-(Formyl-amino) phenoxy-4H benzopyran yl]methanesulfonamide(“T-614”) and liclofelone [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3,dihydro-1H-pyrrolizine-5-yl]-acetic acid, as well as anypharmaceutically active derivatives and pharmaceutically acceptablesalts thereof.

In certain embodiments, the pharmaceutically active component is aninhibitor of inducible NOS (iNOS) selected from the group consisting ofamino-guanidine, N^(G)-Nitro-L-arginine, N^(G)-Monomethyl-L-arginine,N^(G)-(1-Iminoethyl)-L-lysine, N^(G)-Nitro-L-arginine,S-Methyl-L-thiocitrulline, N^(G)-Monomethyl-L-arginine acetate,diphenyleneiodonium chloride, isothiourea derivatives such asS-Methylisothiourea˜, S-Ethylisothiourea, S-Isopropylisothiourea, andS-(2-Aminoethyl)-isothiourea, Monomethyl-L-arginine acetate,2-iminopiperidine; 2,4-Dia-nino-6-hydroxy-pyrimidine;5-chloro-1,3-dihydro-2H-benzimidazol-2-one (FR038251), 1,3(2H,4H)-isoquinoline-dione (FR038470) and 5-chloro-2,4(1H,3H)-quinazolonedione (FR191863).

In certain embodiments, the pharmaceutically active component is a DMARDselected from the group comprising Doxycycline, Chondroitin Sulfate,Methotrexate, Leflounomide (ARAVA®, Aventis), Dimethylnitrosamine,azatriopine, hydroxychloroqine, cyclosporine, minocycline, salazopyrine,penicillamine, aurothiomalate (gold salt), cyclophosphamide, andazathioprine.

In certain embodiments, the pharmaceutically active component is abisphosphonate selected from the group consisting of ibandronate,zoledronate, alendronate, risedronate, ethidronate, chlodronate,tiludronate, minodronate, incadronate, olpadronate and pamidronate.

In some embodiments of the method wherein the alkaline earth metal isstrontium, the method comprises reacting strontium hydroxide with adi-carboxylic acid at a temperature in a range of from about 120° C. toabout 135° C. and at a pressure of from about 1 to about 1.7 bar for atime period of from about 15 min to about 60 min to obtain a strontiumsalt of the employed dicarboxylic acid. The method can further comprisea step of filtering the hot reaction mixture immediately after heatingis stopped to remove precipitated strontium carbonate from the reactionmixture.

In certain embodiments of the method precipitation of the strontium saltfrom the reaction mixture is improved by the addition of 5-60 vol/vol %alcohol, such as 5-40 vol/vol % alcohol or more preferred 10-25 vol/vol% alcohol to the solution. In a specific embodiment, the alcohol isethanol. In another specific embodiment, the alcohol is methanol.

In another aspect, the invention relates to a strontium salt, which isstrontium (L-) digiutamate pentahydrate. In some embodiments, thestrontium salt has a crystal composition as shown in FIGS. 3 and/or 4herein, and/or geometric properties as shown in Table 4, 5 and/or 6herein. The strontium salt may be, for instance, for use in medicine.

In another aspect, the invention relates to a strontium salt, which isstrontium D-glutamate hexahydrate. In some embodiments, the strontiumsalt has a crystal composition as shown in FIG. 7 herein and/orgeometric properties as shown in Table 8 and/or 9. The strontium saltmay be, for instance, for use in medicine.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 shows diffractograms of the x-ray analysis of two strontiumsalts. The top diffractogram shows: Strontium glutamate hexahydrate, assynthesised by strontium hydroxide and L-glutamic acid at hightemperature but using the reaction conditions described in example 2.This salt and the resulting diffractogram corresponds to the strontiumL-glutamate hexahydrate salt previously described (H. Schmidbaur, I.Bach, L. Wilkinson & G. Müller (1989), Chem. Ber. 122; 1433-1438). Thelower diffractogram shows a strontium glutamate hexahydrate saltsynthesized from strontium chloride and L-glutamic acid as disclosed inthe present example. The new strontium glutamate salt has beenidentified as strontium di-L-glutamate pentahydrate comprised of onestrontium ion and two mono-protonated glutamate ions.

FIG. 2 shows the molecular structure of strontium malonate (anhydrous)in the crystalline form as disclosed by Briggman B & Oskasson Å 1977,Acta Cryst. B33; 1900-1906. The crystal is shown with atoms depictedwith arbitrary radii.

FIG. 3 shows the crystal packing of strontium (L-) diglutamatepentahydrate viewed along the b axis. The strontium nine coordination isshown as gray shaded polyhedra. H atoms have been omitted for clarity.

FIG. 4 illustrates the asymmetric unit of Strontium (L-) diglutamatepentahydrate crystals, showing 75% probability displacement ellipsoidsand the atomic numbering. H atoms are represented by circles ofarbitrary size.

FIG. 5 shows a X-ray powder diffractogram of crystals of strontiumglutamate hexahydrate prepared by the method as described in Example 8.

FIG. 6 shows a X-ray powder diffractogram of crystals of strontiummalonate prepared by the method as described in Example 9 and analyzedas described in Example 18.

FIG. 7 illustrates the crystal packaging of strontium D-glutamatehexahydrate (left panel) and asymmetric unit of the crystals (rightpanel) showing 75% probability displacement ellipsoids and the atomicnumbering. H atoms are represented by circles of arbitrary size. In theleft panel the crystals are viewed down the α-axis, with the Srnin-coordination shown as polyhedra.

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses a new method for synthesis and isolationof organic salts of metal-ions, especially of alkaline earth metals. Inthe manufacture method according to the invention a high temperatureand, optionally, pressure is employed to ensure higher yield, purity andreaction speed than obtained with currently known synthesis methods formanufacture of organic salts of alkaline earth metals and alkali metals.

Accordingly, the present invention relates to a method for thepreparation of a metal salt of all organic acid, the method comprisingreacting a hydroxide or a halogen salt of the metal ion with the organicacid (anion) in an aqueous medium at a temperature of about 90° C. ormore such as, e.g., about 100° C. or more, 120° C. or more, or about125° C. or more for a time period of at the most about 60 min such as,e.g. at the most about 30 min or at the most about 20 min such as about15 min.

In a specific embodiment the reaction may be performed in a closedcontainer at a temperature of 100° C. or more and a pressure of 1 bar ormore.

Examples are provided herein demonstrating the importance of reactiontemperature and giving guidelines for establishing the optimumtemperature for a given organo-metallic salt synthesis in particular forthe synthesis of strontium salts. The synthesis allows production ofsome entirely new salts, where time, temperature and pressure are keyparameters of compound purity. The synthesis method is applicable forthe manufacture of most organic salts of metal ions, but in particularcarboxylic acid salts of alkaline earth metals can be made according tothe present invention with higher yield and purity than obtainable byother methods.

A crucial point in the method according to the invention is theavoidance of formation of relatively large amounts of insolublecarbonate. In fact, this is very difficult to avoid as the carbonatesalts have very poor solubility and when formed rapidly precipitate fromsolution thereby contaminating the desired reaction products.Furthermore, the starting materials for synthesis of metallo-organicsalts comprise a metal hydroxide or a metal halogenid (which enableconditions that are favorable for carbonate formation in an aqueousmedium). If the organic acid of the metallo-organic salt is a carboxylicacid, which often be the case, it is generally realized that only gentleheating to slightly higher temperatures than room temperature can beaccepted due to the risk of decarboxylation of the carboxylic acid andsubsequent increase in the carbonate level.

Accordingly, the invention provides a method for the preparation ofdivalent metal salts that enables the use of a much higher reactiontemperature than room temperature, a higher yield of the desired salt(as compared to the known methods) and at the same time keeps theformation of carbonate at a very low limit. The yield of the divalentmetal salt prepared by a method according to the invention is 70% ormore such as, e.g., about 75% or more, about 80% or more, about 85% ormore, about 90% or more or about 95% or more. The amount of precipitatedcarbonate may be less than 1%, such as less than 0.75% or less than 0.5%or even below 0.2% of the amount of desired metallo-organo salt producedby the manufacturing process.

The method according to the invention may further comprise a step offiltering the hot reaction mixture immediately after heating is stoppedto remove precipitated carbonate from the reaction mixture.

Furthermore, the present inventors have found that in order toaccelerate the crystallization of the divalent metal salt, addition ofsmall volumes of an alcohol such as, e.g., methanol or ethanol, such asfrom 5-10 vol/vol % to 50-60% vol/vol induces a significant accelerationof the precipitation of the desired salt. Addition of an alcohol is ofspecial importance in the synthesis of salts with solubility exceeding 2g/l at room temperature

The production methods according to the invention are applicable for awide range of different chemical substances. Of special relevance areapplications where the desired metallo-organic salt is used in productsfor human use such as food-products, ingredients for pharmaceutical use,personal care products such as creams, lotions and toothpaste andvitamins and other nutritional supplements. In such cases, a high purityof the product is desired, and the manufacturing procedure describedhere provides a significant advantage compared to all other availablemethods.

A suitable metal for use in the method according to the invention isselected from metal atoms or ions, which have been tested for or areused for pharmaceutical purposes. Such metal atoms or ions belong to thegroup denoted alkaline metals, alkaline earth metals, light metals,transition metals, post transition metals or semi-metals (according tothe periodic system).

Preferred metals are alkaline earth metals including beryllium,magnesium, calcium, strontium and barium and radium. The method isespecially suitable for metals wherein the production of carbonate isproblematic and unwanted.

As it appears from the examples herein, an especially suitableembodiment of the invention uses a chloride salt of the metal ion as astarting material. However, as it appears from the Examples herein metalhydroxides is also found to be well suited as starting a startingreagents for synthesis of metallo-organic salts.

The molar ratio between the metal ion and the organic acid is ofimportance in order to achieve the best possible yield. Normally, themolar ratio is at least about 0.8:1 such as about 1:1, preferably above1.1:1 such as 1.2:1.

In principle, the organic acid may be any organic acid. In specificembodiments, the organic acid is a mono-, di-, tri- or quatro-carboxylicacid. Examples of suitable organic acids for use in a method accordingto the invention are e.g. acetic acid, C₂H₅COOH, C₃H₇COOH, C₄H₉COOH,(COOH)₂, CH₂(COOH)₂, C₂H₄(COOH)₂, C₃H₆(COOH)₂, C₄H₈(COOH)₂,C₅H₁₀(COOH)₂, fumaric acid, maleic acid, malonic acid, lactic acid,citric acid, tartaric acid, oxalic acid, ascorbic acid, ibuprofenicacid, benzoic acid, salicylic acid, phthalic acid, carbonic acid, formicacid, methanesulfonic acid, ethanesulfonic acid, camphoric acid,gluconic acid, L- and D-glutamic acid, pyruvic acid, L- and D-asparticacid, trifluoroacetic acid, ranelic acid, 2,3,5,6-tetrabromobenzoicacid, 2,3,5,6-tetrachlorobenzoic acid, 2,3,6-tribromobenzoic acid,2,3,6-trichlorobenzoic acid, 2,4-dichlorobenzoic acid,2,4-dihydroxybenzoic acid, 2,6-dinitrobenzoic acid, 3,4-dimethoxybenzoicacid, abietic acid, acetoacetic acid, acetonedicarboxylic acid, aconiticacid, acrylic acid, adipic acid, alpha-ketoglutaric acid, anthranilicacid, benzilic acid, arachidic acid, azelaic acid, behenic acid,benzenesulfonic acid, beta-hydroxybutyric acid, brassidic acid, capricacid, chloroacrylic acid, cinnamic acid, citraconic acid, crotonic acid,cyclopentane-1,2-dicarboxylic acid, cyclopentanecarboxylic acid,cystathionine, decanoic acid, erucic acid, ethylene-diaminetetraaceticacid, fulvic acid, fumaric acid, gallic acid, glutaconic acid, glutaricacid, gulonic acid, glucosamine sulphate, heptanoic acid, hexanoic acid,humic acid, hydroxystearic acid, isophthalic acid, itaconic acid,lanthionine, lauric acid (dodecanoic acid), levulinic acid, linoleicacid (cis, cis-9,12-octadecadienoic acid), malic acid, m-chlorobenzoicacid, melissic acid, mesaconic acid, methacrylic acid, monochloroaceticacid, myristic acid, (tetradecanoic acid), nonanoic acid, norvaline,octanoic acid, oleic acid (cis-9-octadecenoic acid), ornithine,oxaloacetic acid, palmitic acid (hexadecanoic acid), p-aminobenzoicacid, p-chlorobenzoic acid, petroselic acid, phenylacetic acid,p-hydroxybenzoic acid, pimelic acid, propiolic acid, propionic acid,p-tert-butylbenzoic acid, p-toluenesulfonic acid, pyruvic acid,sarcosine, sebacic acid, serine, sorbic acid, stearic acid (octadecanoicacid), suberic acid, succinic acid, terephthalic acid, tetrolic acid,threonine, L-threonate, thyronine, tricarballylic acid, trichloroaceticacid, trimellitic acid, trimesic acid, tyrosine, ulmic acid andcylohexanecarboxylic acid.

In specific embodiments, the organic acid is an amino carboxylic acidsuch as, e.g., a natural or synthetic amino acid.

Other divalent metal salts that may be prepared according to the presentinvention are comprised of a divalent metal ion and an anion selectedfrom the group of pharmaceutically active compounds with an acid oramine group such as: salicylates such as acetyl salicylic acid,piroxicam, tenoxicam, ascorbic acid, nystatin, mesalazin, sulfasalazin,olsalazin, glutaminic acid, repaglinid, Methotrexate, Leflounomide,Dimethylnitrosamine, azatriopine, hydroxychloroqine, cyclosporine,minocycline, salazopyrine, penicillamine, diclofenac, propionic acidssuch as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen,pyrazolones including phenylbutazone, fenamates such as mefenamic acid,indomethacin, sulindac, meloxicam, apazone, pyrazolones such asphenylbutazone, bisphosphonates such as zoledronic acid, minodronicacid, incadronic acid, ibandronate, alendronate, risedronate,olpadronate, chlodronate, tiludronate and pamidronate, COX-2preferential cyclo-oxygenase inhibitors such as celecoxib, valdecoxib,etoricoxib, lumiracoxib, parecoxib, rofecoxib and deracoxib, pantotenicacid, epoprostenol, iloprost, tirofiban, tranexamic acid, folic acid,furosemide, bumetanide, kanrenoic acid, capopril, rasagiline, enalapril,lisinopril, ramipril, fosinopril, trandolapril, valsartan, telmisartan,pravastatin, fluvostatin, atorvastatin, cerivastatin, sulfadiazine,tretionin, adapalen, azelaic acid, dinoproston, levotyroxin, lityronin,doxycyclin, lymecyclin, oxytetracyclin, tetracycline, ampicilin,amoxicillin, clavulanic acid, taxobactam, nalidiksinic acid fusidinicacid and liclofelone [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3,dihydro-1H-pyrrolizine-5-yl]-acetic acid, as well as anypharmaceutically active derivative of the compounds.

Other examples of relevant acids for making strontium salts for use in apharmaceutical composition may be found in WO 00/01692, which is herebyincorporated by reference.

The method according to the invention may be used to prepare a widerange of metal salts. In specific embodiments of the invention the metalsalt may be formed between an organic acid containing at least onecarboxylic acid functional group and an alkaline earth metal selectedfrom the group comprising strontium, calcium and magnesium. Especiallystrontium is regarded as an interesting component in the treatment ofvarious diseases, particularly diseases involving aberrant regulation ofbone and/or cartilage metabolism (see the detailed discussion below)and, in a specific embodiment of the invention the metal is strontium.

To illustrate the potential of the method according to the presentinvention, a detailed description of its application for manufacture oforganic strontium salts is provided. However, this is merely meant toillustrate the potential of the invention and not to limit the scope inany way.

Strontium

Strontium is found naturally exclusively as a non-radioactive stableelement. Twenty-six isotopes of strontium have been described, but onlystable non-radioactive strontium is found on earth. Natural strontium isa mixture of the 4 stable isotopes Sr-84, Sr-86, Sr-87, and Sr-88, ofwhich the isotope Sr-88 is the most common comprising 82.5% of allstable strontium on earth. The average molar weight of naturalnon-radioactive strontium is 87.62 Da. Other known, non-natural,isotopes of strontium are radioactive, and of these radioactivestrontium isotopes, Strontium-90 and Sr-89 are the most important. Theyare powerful beta-emitters with several commercial uses. Sr-89 isutilized in some medical applications, whereas Sr-90 finds it main usein auxiliary nuclear power devices for use in very special applicationssuch as generating electric power to satellites and remote powerstations. The medical use of Sr-89 is mainly related to the potential ofstrontium to target mineralized bone tissue where the radioactive Sr-89isotope is employed to destroy bone tumors.

In nature, strontium is practically always found in the oxidized stateas a di-cation and consequently is found as a salt, complexed withinorganic anions such as carbonate, sulphate and phosphate. A relativelylimited number of strontium salts have been subjected to detailedchemical characterization, with full resolution of structure andchemical properties. Generally the strontium salts studied showproperties similar to the corresponding salts of other second main groupalkaline earth metals. This means that properties of a given strontiumsalt can be expected to mimic the corresponding calcium, magnesium andbarium salts.

The naturally occurring salts of strontium, such as the carbonate andsulphate salts, have very low water solubility (0.15 g/l or below atroom temperature). This solubility is lower than the correspondingcalcium and magnesium salts, which is in accordance with the ionic andelectropositive nature of strontium being greater than that of calcium.An important example of an exemption to the rule is found in thesolubility of hydroxides where strontium hydroxide is the more soluble.Thus, the general observation is that the aqueous solubility of mostinorganic strontium salts is lower than the analogous calcium salts.This is a result of the lower polarizing power of ionic strontiumcompared to calcium and magnesium ions, which have a higher polarizingpower due to their smaller nuclear radii (0.99 Å for calcium comparedwith 1.12 Å for strontium). However, it must be emphasized that manyinorganic strontium salts are highly soluble. As examples, strontiumchloride, strontium hydroxide, strontium nitrate and strontium oxide arehighly soluble with solubility in the range from 225-800 g/l in water.For some strontium salts, such as the hydroxide salt, the solubility ishigher than the corresponding calcium or magnesium salts.

Organic strontium salts have been described, but literature reports ofthis type of compounds are limited to rather few substances. All theseare strontium salts of anions containing carboxylic acids. Thephysiochemical properties of organic strontium salts have been reportedto be similar to the corresponding magnesium, calcium and barium salts(Schmidbaur H et al. Chem. Ber. (1989) 122: 1433-1438). Strontium saltsof carboxylic acids are crystalline non-volatile solids with strongelectrostatic forces holding the ions in the crystal lattice. Mostcrystalline forms of organic strontium salts contain various amounts ofcrystal water, which serves to coordinate with the strontium ions in thecrystal lattice. The temperature required for melting these salt aremost often so high, that before it can be reached the carbon-carbonbonds of the organic anion breaks and the molecule decomposes, generallyat a temperature of 300-400° C. (Schmidbaur H et al. Chem. Ber. (1989)122: 1433-1438).

All alkaline earth metal salts of carboxylic acids are soluble to someextent in aqueous solutions, but the solubility of the specific saltsvary considerably depending on the size and hydrophobicity as well aselectrostatic properties of the organic anion. One of the simplestorganic carboxylic acids, acetate, makes well-defined crystalline saltsof strontium, which are highly soluble in water (solubility 369 g/l atroom temperature). Larger organic anions usually have considerable lowersolubility, depending on the hydration enthalpy and lattice enthalpy ofthe salt. However, as various strontium salts would not necessarily formthe same type of crystal structure and their crystal lattice energiesare unknown, it is not possible to make theoretical calculations of thesolubility of such salts, but they will have to be determinedempirically. Furthermore, a given salt may exist in different crystalstructures, where important properties, such as the amount of boundcrystal water varies, and thus different crystal forms will havedifferent lattice and hydration enthalpies and thus solubility.

Properties of Carboxylic Acid Salts of Strontium

Carboxylic acids salts of divalent earth metals such as strontium, andespecially di-carboxylic acids have some unique properties, as they canhave a partial chelating effect in solution. In these cases the saltexists in solution as a complex in which the divalent metal ion is boundin a complex to the carboxylic groups of the anion. Such complexationmay be important in biological systems, where the alkaline earth metals,especially calcium and magnesium, play vital physiological roles. Amajority of divalent metal ions may exist in complex bound form in theaqueous environment in biological systems, rather than in a free andun-bound ionic form. Complex formation constants with the alkaline earthmetals in aqueous solution are higher for amino acids than forhydroxy-carboxylic acids and the related non-carboxylic acids, whichsuggest that the amino group may play a role in the complex formation.Generally, the differences in association constants and hydrationenthalpy for the various ligands become smaller as the radius of themetal increases. Thus, the stability of strontium complexes withdi-carboxylic acid is lower than the stability of the comparablecomplexes with calcium and magnesium. This means that in aqueoussolutions the chelating di-carboxylic acids will have a propensity topreferentially bind calcium and magnesium rather than the larger ions ofstrontium and barium.

Few organic strontium salts have found commercial applications, and thusno such compounds are available in large-scale chemical manufacture(>1000 kg batch size). However, recently, the strontium salt of thetetra-carboxylic acid, ranelate, has been developed for pharmaceuticaluse in treatment of metabolic bone diseases such as osteoporosis. Thechemical properties of strontium ranelate are similar to manydi-carboxylic acid salts of strontium. In water it has a solubility of0.76 μl at 22-24° C., with slight increases in solubility at highertemperatures and lower pH. In aqueous solutions the ranelate ionfunctions as a chelator, complexing divalent metal ions as describedabove. The core 3-cyano-4-carboxymethylthiophene structure of theranelate ion is chemically stable under physiological conditions,although the nitrile group may undergo hydrolysis to form various□-hydroxyacids or unsaturated acid derivatives of ranelate.

Synthesis of Carboxylic Acid Salts of Strontium

Organic-strontium salts of carboxylic acid anions can be synthesized bya number of different pathways. A conventional method for preparation ofsuch organic strontium salts is to utilize the reaction between anorganic acid and strontium hydroxide in an aqueous solution. As anexample, the reaction scheme below shows this neutralization reaction ofmalonic acid and strontium hydroxide salt:Sr²⁺(aq)+2 OH⁻(aq)+C₃H₂O₄ ²⁻(aq)+2H⁺ (aq)→Sr (C₃H₂O₄²⁻(aq)+2H₂O(l)  Equation 1

After the reaction, which occurs rapidly upon dissolution of the solids,the suspension of dissolved strontium malonate can then be induced toprecipitate by evaporation of water and subsequent up-concentration ofthe salt. Crystals of strontium malonate will slowly form andprecipitate from the solution.

An alternative approach is to utilize the sodium or potassium salt ofthe appropriate carboxylic acid anion and strontium chloride. As allorganic strontium salts will be less soluble than the highly solublechloride salt, the organic strontium salt will precipitate under theseconditions leaving NaCl and excess SrCl₂ in the solution. The equationbelow exemplifies this reaction scheme using as an example the reactionbetween SrCl₂ and sodium-malonate, where reaction products are added inequimolar amounts.Sr²⁺(aq)+2 Cl⁻(aq)+2 Na⁺(aq)+C₃H₂O₄ ²⁻(aq)→Sr (C₃H₂O₄²⁻(aq)+Cl⁻(aq)+Na⁺(aq)  Equation 2

In both the alternative synthesis pathways, re-crystallizations arelikely to be required in order to obtain the desired strontium salt insufficiently pure form. In turn the yield will decrease as a consequenceof loss of material during re-crystallization owing to the lack ofcomplete precipitation of strontium from solution and from formation ofstrontium carbonate that precipitate and due to the very low solubilityof metal carbonates makes the precipitated strontium unavailable forfurther reaction. In alkaline solution, carbonate is formed bydissolution of atmospheric carbon dioxide, according to:CO₂(g)+2 OH⁻(aq)→CO₃ ²⁻(aq)+H₂O(l)  Equation 3

Since strontium carbonate is readily formed and has a low solubilityproduct, Equation 3 is displaced towards the right, which extractsstrontium from the product carboxylate, that is, Equation 1 (or 2) isdisplaced to the left. Thus, repetitive re-crystallisations will reducethe yield of the desired strontium carboxylate, while increase thepresence of contaminating strontium carbonate.

The reaction schemes shown above (Equations 1 and 2) are depicting thefinal reaction for manufacture of organic strontium salts involving asimple reaction of an inorganic strontium salt with the desired organicanion in either free acid form or available as a salt. Thus, in order tocarry out these reactions it is required that the organic acid iscommercially available. In the case of more complex and/or unusualanions, they will have to be synthesized prior to the preparation of thestrontium salt and formation of the strontium salt by reaction schemesas outlined above may then be incorporated in the last synthesis step.In either case the methods and procedures disclosed in the presentpatent may be of great use in improving the yields and purities of thedesired reaction products

According to the method of the present invention, manufacture of anystrontium salt, or salt comprised of an organic anion and a metal cationsuch as e.g. an alkaline earth metal or alkali metal cation, especiallyan alkaline earth metal cation, may be synthesized more efficiently withhigher yield, better purity and shorter processing times by performingthe reactions at elevated temperature, under inert atmosphere andoptionally with higher pressure. In specific the present inventorsdemonstrate a dramatic improvement in yield and purity of strontiumsalts produced in this way compared with previous synthesis methodsdisclosed in the prior art literature.

The present manufacturing method can be used for production of strontiumsalts of dicarboxylic organic anions, which may be used in thepreparation of prophylactic and/or therapeutic treatments of metabolicbone diseases.

High strontium intake has in several animal studies been associated withalterations in bone mineralization and increased skeletal strength. Theeffect is believed to be due to a stimulatory effect of strontium onpre-osteoblastic cell maturation, migration and activity, and a director matrix-mediated inhibition of osteoclast activity by strontium. Inother words, strontium both works as an anti-resorptive and an anabolicagent on bone tissue.

Various salts of strontium are known from the prior art, such as, e.g.,strontium ranelate (distrontium salt of2-[N,N-di(carboxymethyl)amino]-3-cyano-4-carboxymethyl-thiophene-5-carboxylicacid) described in EP-B 0 415 850. Other known strontium salts are e.g.,strontium tartrate, strontium phosphate, strontium carbonate, strontiumnitrate, strontium sulfate and strontium chloride. The present inventorshave found that strontium salts of some dicarboxylic acids, such asstrontium malonate, strontium fumarate, strontium succinate, strontiumglutamate and strontium aspartate are more soluble than otherdicarboxylic strontium salts of similar molecular size. In pure aqueoussolutions of such salts, strontium exists in partly complexed form. Whenadministered to an animal such as a mammal, i.e. a rat, dog, monkey orhuman, ionic strontium as well as strontium complexed to the carboxylicacid anion will be taken up from the intestinal lumen by both passiveand active transport mechanisms. In this case strontium will bedisplaced from the complexes by available calcium and magnesium whichforms much more stable complexes with the ionized amino acids. Certaindicarboxylic acids may be especially suited for prophylactic and/ortherapeutic interventions in bone disease as they may act topreferentially bind/complex with available free calcium, thus promotingboth the intestinal uptake of the calcium ion, and physiological actionof the ion, in particular its role in regulation of bone turnover.Specific salts of interest are strontium salts formed with acids likefumaric acid, maleic acid, malonic acid, lactic acid, citric acid,tartaric acid, ascorbic acid, salicylic acid, acetyl-salicylic acid,pyruvic acid, L- and D-aspartic acid, gluconic acid, L- and D-glutamicacid, ranelic acid, alpha-ketoglutaric acid, arachidic acid,cyclopentane-1,2-dicarboxylic acid, malic acid, myristic acid(tetradecanoic acid), pyruvic acid, sarcosine, serine, sorbic acid,threonine, thyronine and tyrosine.

In a specific embodiment the salts formed are strontium malonate,strontium lactate strontium succinate, strontium fumarate, strontiumascorbate in L and/or D-form, strontium aspartate in either L and/orD-form, strontium glutamate in either L- and/or D-form, strontiumpyruvate, strontium tartrate, strontium threonate, strontium glutarate,strontium maleate, strontium methanesulfonate, strontiumbenzenesulfonate and mixtures thereof.

Novel strontium salts are also provided by the present invention such asstrontium L-diglutamate pentahydrate and strontium D-glutamatehexahydrate. These salts are described below for the first time and theconvenient manufacture in high purity of these previously undisclosedand/or difficult-to-manufacture alkaline earth metal salts of organicacids demonstrate the potentials of the disclosed manufacturing methodfor efficient synthesis of difficult organo-metallic salts.

Strontium Malonate

Strontium malonate has previously been described in the literature.However, synthesis methods for manufacture of strontium malonate in pureform have not previously been described in detail.

In one report an anhydrous strontium malonate salt was described. Theauthors reported that slow evaporation at room temperature over severaldays of an aqueous solution of malonic acid and strontium hydroxideresulted in colorless single crystals. These crystals were analyzed byX-ray crystallography and shown to be orthorhombic unit cell with nocrystal water bound (Briggman B & Oskasson A 1977, Acta Cryst. B33;1900-1906). FIG. 2 and Table 1 below give a schematic presentation ofthe resolved crystal structure of the anhydrous strontium malonate salt:

TABLE 1 Distances [Å] and angles [°] for the malonate ion in theanhydrous crystalline form of strontium malonate as described byBriggman & Oskasson 1977. For atom nomenclature please refer to FIG. 2.Distances C(1)-C(2) 1.529(5) C(2)-H(1)  1.04(5) C(2)-C(3) 1.525(5)C(2)-H(2)  0.89(5) C(1)-O(1) 1.262(4) O(1)-O(2) 2.505(3) C(1)-O(2)1.252(4) O(3)-O(4) 2.207(3) C(3)-O(3) 1.250(4) O(2)-O(4) 2.924(3)C(3)-O(4) 1.270(4) Angles C(1)-C2(2)-C(3) 112.5(3) C(2)-C(3)-O(3)119.3(3) O(1)-C(1)-C(2) 117.2(3) C(2)-C(3)-O(4) 118.4(3) O(2)-C(1)-C(2)120.2(3) O(3)-C(3)-O(4) 122.4(3) O(1)-C(1)-O(2) 122.6(3) H(1)-C(2)-H(2)  113(4)

At least two crystalline forms of strontium malonate exist, oneanhydrous as described in FIG. 2 and Table 1 above and a form with onemolecule of water pr. unit cell in the crystal. In situations where ahigh strontium content of the salt is desired, such as in pharmaceuticalapplications, the use of the anhydrous salt is preferred, as strontiumconstitutes 45.7% of the salt on a molar basis. Thus a manufacturingprocedure that allows reproducible and controlled manufacture of thissalt in high purity and yields is of great value.

In the synthesis of strontium malonate, the total yield of the productdepends on temperature and on time of synthesis. Thus, the synthesismight be improved by testing the synthesis in an autoclave system, wherethe temperatures are maintained below the temperature of decompositionof the organic anion moiety of the desired strontium salt. As anexample, malonic acid decomposes under neutral or acid conditions at132-134° C., and thus synthesis of strontium malonate must be performedat temperatures below 132° C. However, alkaline conditions enhance thestability of malonate, which may enable synthesis at temperatures abovethe normal temperature of decomposition.

Of further relevance is the fact that carboxylates may decarboxylateupon heating (O) and release gaseous carbon dioxide. The reactionsdepicted in Equations 4 and 5 demonstrate that decarboxylation ofmalonic acid is facilitated by addition of acid that promotes thereaction through an intermediate of a carbanion:HOOCCH₂COO⁻(aq)+Q→CO₂(g)+HOOCCH₂ ⁻(aq)  (4)HOOCCH₂ ⁻(aq)+H⁺(aq)→CH₃COOH(aq)  (5)

At low temperatures, the decarboxylation is not pronounced because thereaction of Equation 4 is slow. However, by elevating the temperatureand adding acid, the reaction may proceed to completion. In thesynthesis of strontium malonate, it was found by the optimizationprocedure that it could be produced in high yields by using sealedreaction vessels with a gas pressure of either an inert gas or steamunder alkaline conditions. This result of the optimization complies withthe reactions of Equations 4 and 5, which predict that they are bothdisplaced to the left, thus favoring the stability of malonate ions.Steam and argon were used to lower the risk of decarboxylation, butother inert gases could be used as well.

Accordingly, strontium malonate may be synthesized by reacting asuspension of malonic acid with strontium hydroxide at a temperaturemaintained at or above 1000 but below 130° C. to avoid decomposition ofmalonic acid, and at an elevated pressure (at or above 1 bar) in aclosed container. By this method a high yield of pure strontium malonatecan be obtained after a reaction time of only 15 min, and a singlefiltration step.

Strontium Glutamate

Strontium L-glutamate has previously been prepared by reacting strontiumhydroxide with L-glutamic acid under reflux for 3 hours with asubsequent cooling and slow crystallization over a period of up to 2weeks.

In a method according to the present invention strontium L-glutamatehexahydrate has been prepared by reacting strontium hydroxide withglutamic acid at a temperature in a range of from about 120° C. to about135° C. and at a pressure of from about 1 to about 1.7 bar, optionallyunder an inert gas atmosphere, for a time period of from about 15 min toabout 60 min to obtain strontium glutamate. The method may furtherinvolve a step of filtering the hot reaction mixture immediately afterheating is stopped to remove precipitated calcium carbonate from thereaction mixture. Further details and guidelines for optimization of thereaction appears from Example 8.

As mentioned above, by use of the method according to the presentinvention, the present inventors have prepared a new glutamate salt ofstrontium (strontium L-diglutamate pentahydrate) that is distinct fromthe known strontium glutamate.

Details concerning the preparation and crystal structure of this novelsalt is found in Example 5 herein. In the following is given detailswith respect to this novel salt.

The X-ray crystalographic analysis (FIG. 1) revealed that thesynthesized strontium glutamate salt was distinct from the previouslydescribed strontium L-glutamate hexahydrate salt described in FIGS. 1and 2 and Tables 2 and 3.

Another novel strontium glutamate salt that has been produced by themethod according to the present invention is strontium D-glutamatehexahydrate. The properties and crystal structure of this salt isdescribed in Example 10.

Both in the case of strontium D-glutamate hexahydrate and strontiumdi-L-glutamate pentahydrate, the rapid production of these two novelorganic salts of strontium in high purity and homogeneous crystallineformapplicable for X-ray analysis by the high temperature productionmethod described in the present patent, provides an exemplification ofthe applicability of the method for producing difficult organo-metallicsalts.

Strontium Aspartate

Strontium L-aspartate has also previously been prepared by reactingL-aspartic acid with strontium hydroxide. The reaction was performedover 3 hours under reflux, and the resulting reaction mixture wasallowed to cool over three days to initiate crystal formation. Theresulting strontium L-aspartate crystals were subjected to X-raycrystallography in order to elucidate the crystal structure (please see:H. Schmidbaur, P. Mikulcik & G. Müller (1990), Chem. Ber. 123;1599-1602). The investigations revealed that the isolates strontiumL-aspartate salt was formed in the trihydrate form.

To summarize, the present inventors have found that different strontiumsalts require different synthesis pathways, and for some strontium saltsthey have identified optimized synthesis and manufacturing procedures.Of particular relevance for the present invention, it has been foundthat synthesis of strontium salts of the di-carboxylic amino acidsaspartate and glutamate (in either D- or L-form) and strontium malonateis very difficult when following the conventional reaction pathways, andgenerally results in low yields and purity of the obtained crystallinesalt. In order to facilitate large-scale manufacture of pure strontiumsalts of dicarboxylic amino acids to carry out e.g. pharmaceutical use,the present inventors have studied various synthesis pathways of theseparticular strontium salts. Thus, it has surprisingly been found thatsynthesis of well defined and pure strontium glutamate in hexahydrateform is most conveniently performed with the free acid form of glutamateand strontium hydroxide and requires elevated temperatures, such astemperatures above 80° C., or more preferred 100° C. or even 120° C. ormost preferred more than 130° C. (see Examples 5-17). Furthermore, theyhave found that addition of small volumes of alcohol can accelerate thecrystal-formation of dissolved aqueous organic strontium salts (seeExample 3). Furthermore, in the present invention new crystalline formsof strontium salts of dicarboxylic acids are disclosed (see Example 5, 6and 10).

The strontium salts prepared according to the invention may be used inmedicinal products, such as creams, lotions, ointments, tablets,capsules, gels etc. As mentioned above strontium is believed to have aneffect on cartilage and/or bone conditions and/or other conditions, thusthe salt may be used for the preparation of a pharmaceutical compositionfor the treatment and/or prophylaxis of a cartilage and/or a bonecondition and/or a dysregulation of cartilage and/or bone metabolism ina mammal, such as osteoporosis, healing of skeletal fracture,stabilization of orthopaedic implants, osteoarthritis, rheumatoidarthritis, Legg-Calve-Perthes disease, steroid induced osteoporosis,bone loss induced by other therapies such as chemotherapy or highlyactive anti-retroviral therapy (HAART) or systemic lupus erythomatosus(SLE) The pharmaceutical composition may further comprise one or morephysiologically acceptable excipients.

For the treatment and/or prophylaxis of a cartilage and/or bone diseaseand/or conditions resulting in a dysregulation of cartilage and/or bonemetabolism in a mammal, the possibility of administering various amountsof strontium and, if relevant malonate, alpha-ketoglutarate or an aminoacid like e.g. glutamic acid and/or aspartic acid, respectively, may bedesired. The amount of strontium (and, if relevant e.g. malonate,alpha-ketoglutarate or an amino acid) in a pharmaceutical compositionaccording to the invention may be adjusted by adding an additionalamount of strontium in the form of a strontium-containing compound tothe composition. The strontium-containing compounds may be selected fromthe salts mentioned above.

In the following is given a more detailed description of the preparationof individual salts according to the invention. All details with respectto strontium apply also for all the other alkaline earth metal salts orsalts of alkali metals according to the invention.

Furthermore, the details and particulars described above for strontiumsalts apply mutatis mutandis to the individual strontium salts, wheneverrelevant, as well as details and particular described below for theindividual strontium salts apply mutatis mutandis to the strontium saltsin general, whenever relevant. Furthermore, the methods of the presentinvention apply with equal relevance to the manufacturing of othermetallo-organic salts.

EXAMPLES Example 1—For Comparison Use of a Known Method for Preparationof Crystalline Salts of Strontium by Precipitation from DissolvedStrontium Chloride and Dissolved Sodium Salts of the AppropriateCarboxylic Anions

In a glass-beaker of 100 mL volume, 5 g of the sodium salt of thecarboxylic acid was dissolved in a small volume of water that wasslightly heated at temperatures not greater than 30-50° C. The finalvolume was 25-50 mL. In another beaker 10 g of SrCl₂ (SrCl₂ hexahydrate,Sigma-Aldrich 43, 966-5) was dissolved in 100 mL of water. This lattersolution was slowly decanted into the first solution of the dissolvedsodium salt. The transfer continued until an initial cloudiness wasobserved, which resulted in a total volume of 50-100 mL. The solutionwas incubated at room temperature (22-24° C.) for several days untilsignificant amounts of crystallized precipitate of the organic strontiumsalt appeared.

The reaction that proceeds is exemplified by the reaction betweenstrontium ions and sodium fumarate (reaction schemes (a) and (b)):NaOOCCHCHCOONa(s)+H₂O(l)→⁻OOCCHCHCOOH(aq)+2 Na⁺(aq)+OH⁻(aq)  (a)⁻OOCCHCHCOOH(aq)+Sr²⁺(aq)→Sr (OOCCHCHCOO(aq)+H⁺(aq)  (b)

After the precipitation, the solution was filtered on a Büchner funnelusing a suction flask and the crystals were flushed in small volumes ofethanol. Crystals of some of the salts were very soluble, so in order toimprove the yield of crystals, the solution was allowed to rest longer,such as at least 30-60 min. Repeated crystallization resulted in yieldsof approx. 50%. Strontium salts of L-aspartate and of lactate were verysoluble, with solubility exceeding 25 g/l in water at room temperature.

The lactate and L-glutamate salts of strontium were precipitated fromsolutions with an excess of strontium chloride and large crystals of thelactate salt were achieved by slow evaporation of the solvent.

Example 2—For Comparison General Method for Preparation of CrystallineSalts by Neutralization of Carboxylic Acids with Strontium Hydroxide

A small amount of the appropriate organic acid proper (0.75-3 g, seetable below) was dissolved in water by heating to temperatures between30° C.-50° C. Then, strontium hydroxide (Sigma Aldrich, Sr (OH)₂*8H₂O,MW 265.71, CAS no. 1311-10-0, approx. 10 g/L) was slowly added. Then, amagnetic stirring rod was added and the stirring and gentle heating(i.e. 30-50° C.) of the suspension was started. After some time, thesolution clarifies and all the solid material dissolves. The heating ismaintained, and after three hours of incubation, the solution isfiltered while hot on a Büchner funnel. Very small amounts of impuritieswere left in the filter.

The filtrate was subsequently allowed to cool at room temperatureovernight, which resulted in growth of fine-powdered crystals of thedesired strontium salt. Further purifications of the salts can beperformed by repeated re-crystallizations (Table 2).

TABLE 2 Amounts of start reagent used for organic strontium saltsynthesis and recoveries in the synthesis of eight specific organicstrontium salts following the general reaction pathway with free-acidforms of the anion, and strontium hydroxide Strontium salt of AmountEstimated Melting Crystal (free acid used): Sr(OH)₂ *8H₂O Free acidobtained Yield * Temp. Solubility structure Fumarate¹ 2.044 g 1.140 g0.999 g 21% >380° C. Yes No α-ketoglutarate² 2.017 g 1.441 g 0.828 g16% >380° C. Yes No Succinate 2.098 g 1.177 g 0.958 g 20%  230° C. YesYes L-ascorbate³ 2.094 g 1.805 g 2.005 g 32% >380° C. Yes No L-glutamate2.017 g 1.453 g 0.175 g  4% >380° C. Yes Yes Citrate 2.057 g 1.918 g1.123 g 15% >380° C. Yes Yes L-Aspartate 2.190 g 1.316 g 0.167 g 3% >380° C. No No Tartrate 2.070 g 1.502 g 2.005 g 36% >380° C. Yes YesNotes * Recovery calculated in % of the strontium content in Sr(OH)₂*8H₂O and a stoichiometry that corresponds to the minimum content of thecorresponding acid, e.g. a 1:1 ratio in the tartrate. The strontiumsalts of Table 2 (above) was characterised by powder x-raycrystallography and the corresponding diffractograms (not shown) showedthat the product were relativelyimpure and of poor quality (i.e.heterogeneous crystal forms). Accordingly, the maximum yield of theroom-temperature synthesis was evaluated to be 30%, which was calculatedfrom the magnitude of characteristic peaksin the x-ray diffractograms.Weights were thus multiplied by a factor 0.3, as to obtain the estimatedrecovery and molecular weights of the strontium salts were used with therelevant amounts of bound crystal water. Although imprecise, the methodreveals that the white powders of Table 2 did not contain high yields ofthe desired product. The remaining fraction ofthe product mainlyconsisted of unreacted reagents (i.e. strontiumhydroxide) and strontiumcarbonate. If the strontium salts of Table 2 contained six watermolecules in the crystal structure than the yield would be reduced evenfurther by some 10-50%, as compared to the values presented. Theseestimates and difficulties in determination results from formationsubstantial amounts of strontium carbonate when the salts were separatedby re-crystallisation. 1) Fumaric acid is insoluble in water, andethanol is added to the suspension until complete solubilization isachieved. The synthesis is continued with this material. 2) Thestrontium-AKG salt has a slight brownish appearance. 3) In addition tothe indicated amounts of strontium hydroxides and L-ascorbate anadditional 4.087 g SrCl₂*6H₂O dissolved in water is added to thereaction mixture.

In conclusion, the methods known for the preparation of strontium saltsresult in a relatively poor yield (at the most less than 40%).Furthermore, the data in this example demonstrates that strontiumcarbonate formation, heterogeneous crystal formation and presence ofunreacted starting products in the reactant product is a generalphenomenon when synthesizing strontium salts by methods disclosed in theprior art literature. In the following Examples is given guidance forhow to prepare strontium salts with a higher yield. The examples givenbelow are intended for illustrative purposes and are not constructed tolimit the invention in any way. Furthermore, a person skilled in the artcan find guidance for preparation of other alkaline earth metal salts ororgano-metallic compounds of interest according to the presentinvention.

Example 3 Improvement of Known Synthesis Methods for MakingMetallo-Organic Salts by Using Ethanol Precipitation

As an improvement of the method described in Examples 1 and 2, thepresent inventors have found that in order to accelerate thecrystallization, addition of small volumes of an alcohol such as, e.g.,methanol or ethanol, such as from 5-10 vol/vol % to 50-60% vol/volinduces a significant acceleration of the precipitation of the desiredstrontium salt. Addition of ethanol is of special importance in thesynthesis of strontium salts with solubility exceeding 2 g/l at roomtemperature (22-24° C.), and will thus provide a substantial benefit forthe synthesis of strontium salts of L-aspartate, L-glutamate andlactate. In order to reach the required product within a short period,it was essential to observe an initial crystallization or an initialdimness in the solution right from the first stage.

In the following example is given guidance for determination of thesolubility of strontium salts in order to obtain information on whetheralcohol precipitation advantageously can be applied to speed up andincrease the crystallization of the specific strontium salt during itspreparation according to the present invention.

Example 4 Determinations of Solubility of Organic Strontium Salts

Synthesis of Strontium Salts

The great majority of strontium salts could be obtained by reacting thesodium salt of the organic acid with strontium chloride following thegeneral synthesis method described in Example 1. However, strontiumcitrate, strontium tartrate, strontium succinate and strontium□-ketoglutarate for the solubility investigations was obtained bysynthesis from the free acid forms of the carboxylic acid and strontiumhydroxide as described in Example 2. The solubility of the organiccarboxylic acid strontium salts, were measured in purified water. Thesolubility of these salts was also measured as a function oftemperature. This was performed by incubating the saturated solutions ofthe salts in temperature controlled incubators. Furthermore, thesolubility of the salts was studied in pure distilled water as well as a0.05 M ammonium carbonate buffered solutions, with a physiological pH of7.5.

The buffered solutions were immersed into a water-bath temperaturecontrolled at either room temperature (22-24° C.), at 30° C. or at 40°C. The test tubes were stirred and the solutions were subsequentlyincubated in an incubator with constant temperature for 24 hours. Inorder to eliminate the potential influence of any remaining strontiumchloride on the determination of solubility, all the precipitate wascollected at the bottom of the test tubes and the solutions above theprecipitate were carefully removed and substituted by fresh solutions.After substitution of the solutions, the test tubes were stirred againand allowed to rest for another 24 hours. From these solutions, thedissolved proportions of the strontium salt were collected in volumes of1 mL at the specified temperature. The solutions were diluted to 50 mLbefore analysis by Flame Atomic Absorption Spectrometry (F-AAS). Beforesubsequent series of sampling, the solutions were equilibrated at thenext temperature for 24 hours.

Analysis of Strontium by Flame Atomic Absorption Spectrometry F-AAS

Two methods were used for quantification of strontium in solutions:Flame Atomic Absorption Spectrometry (F-AAS), and the more sensitiveinductively-coupled-plasma-mass spectrometry (ICP-MS). For mostinvestigations, the F-A-AS method had sufficient sensitivity.

Some of the very soluble strontium salts were further diluted beforeanalysis by F-AAS. The measurements were performed by using aPerkin-Elmer 2100 equipped with a hydrogen lamp for correction of thebackground signal. Strontium was measured at a slit with of 0.2 nm, thewavelength was 460.8 nm operated at an energy of 58 and a current of 8mA.

Temperature and pH Influence on Organic Strontium Salt Solubility

For the majority of the organic strontium salts listed in Table 3,temperature changes in the interval from 20-40° C. had only littleinfluence on solubility (Table 3). However, for strontium L-glutamate asignificant influence of temperature on solubility was observed in therange between 20° C. and 40° C. The solubility of this salt increasedmore than three-fold in the investigated interval in contrast to mostother salts. It is noted, that the solubility under physiologicalconditions (37° C.), is of relevance for the pharmaceutical use of thesubstances, and thus the surprising increase in strontium glutamatesolubility at higher temperature may have great potential therapeuticimplications.

The solubility of the strontium salts in an ammonium carbonate bufferedsolution of pH 7.5 was generally higher than the solubility determinedin pure water (Table 3). However, there were some notable exceptions,such as strontium maleate, which had decreased solubility in thebuffered solution. Accordingly, it was found most relevant to comparethe solubility of the strontium salts by comparing the values obtainedin water, as shown in Table 3.

Relative Solubility

The water-solubilities of the organic strontium salts at roomtemperature and at 40° C., are listed in table 3. The strontium salts ofL-aspartate and of lactate had solubilities exceeding 50 g/l hamperingexact determination of solubility with the employed experimentalprocedures.

The results are in agreement with the observations during the synthesisexperiments where the citrate, the fumarate and the tartrateprecipitated instantly when synthesized by the production proceduresdescribed in Examples 1 and 2. This is indicative of a poor solubilityof these strontium salts, as apparent by the lower solubility of thesesalts compared to the other organic strontium salts at both 22° C. and40° C.

The glutamate salt showed a higher solubility than the other salts,especially at a temperature of 40° C. During the synthesis of this salt,the present inventors found a significant improvement in the yield ofthe salt by adding alcohol to the solution, as described in Example 3.The addition of alcohol promoted the initiation of crystal growth. Theother studied strontium salts only precipitated after evaporation of thesolvent for a few days at room temperature. Addition of alcohol was notrequired to initiate crystal formation and precipitation, but itsignificantly promoted the precipitation and thus improved upon thesynthesis method and the yields of the desired salts.

TABLE 3 Relative solubility in water buffered solutions at pH 7.5 at 40°C. and room temperature (22-24° C.) of the investigated Strontium-salts,as determined by F-AAS. SOLUBILITY AT ROOM STRONTIUM TEMPERATURESOLUBILITY SALT (22-24° C.) (mg/L) AT 40° C. (mg/L) Anion In water pH7.5 In water pH 7.5 Malonate** 1474 2816 1441 2127 L-glutamate** 21113022 7093 7195 L-aspartate** >25000 >25000 >25000 >25000 Pyruvate* 22041946 1929 1829 □-ketoglute rate** 1316 2252 3534 3809 Fumarate** 5711215 444 977 Maleate** 3002 1680 2527 1457 Tartrate** 883 1831 1028 1400Ranelate**** 760 890 1450 1970 Succinate** 1137 926 1116 2233 Citrate***107 388 147 430 *Mono-carboxylic acid **Di-carboxylic acid - theglutamate salt is the hexahydrate salt ***Tri-carboxylic acid****Tetra-carboxylic acid

Example 5 Preparation of a Novel Salt, Strontium (L-) DiglutamatePentahydrate, by Synthesis at 100° C. According to the Invention

Initially, a suspension of glutamic acid (white colored) is prepared byadding 100 mL of millipore water to 14.703 g (0.1 moles) of solidL-glutamic acid (Sigma Aldrich, C₅H₉NO₄, MW 187.14 g/mole, CAS no.142-47-2, lot. no. 426560/1, filling code 43003336) in a 250 mL beaker.To this suspension was added 26.66 g (0.1 moles) of solid SrCl₂ (SrCl₂hexahydrate, Sigma-Aldrich 43, 966-5, MW 266.6). Then, a magneticstirring rod was added and the stirring and heating was started, andmaintained until the suspension reached the boiling point. The finalsuspension is also opaque white colored and the stirring is sustained bymaintaining a medium rotation rate of the stirring apparatus. In orderto prevent carbon dioxide from entering the solution, the beaker wascovered by a covering glass.

After some minutes of boiling and stirring, the solution clarified andall the solid material dissolved. The boiling was maintained, andadditional water was added when required, as to replace the water lostby boiling. After three hours of boiling, the solution was filteredwhile boiling on a Büchner funnel. Very small amounts of impurities wereleft in the filter. The filtrate was subsequently allowed to cool toroom temperature, ethanol was added, which resulted in growth offine-powdered crystals of strontium L-diglutamate pentahydrate.Precipitation of the final product progressed in the filtrate within anhour. The product was filtered and dried at 110° C. in an oven for ½hour followed by drying 12 hours in a dessicator over silica orange.Before analysis by x-ray crystallography and by FAAS, the salts wereground by a mortar to fine powder.

The X-ray crystalographic analysis (see FIG. 1) revealed that thesynthesized strontium glutamate salt was distinct from the previouslydescribed strontium L-glutamate hexahydrate salt (H. Schmidbaur, I.Bach, L. Wilkinson & G. Müller (1989), Chem. Ber. 122; 1433-1438). Thestrontium glutamate hexahydrate described previously in the literatureby Schmidbaur et al. was reported to have very low solubility (0.023g/l), wheras the strontium glutamate salt prepared by the methoddisclosed in the present example had a solubility above 2 g/l. Thislater parameter is very important for potential medical use of thestrontium salt as described in the present invention. The salt wasidentified as a new glutamate salt of strontium: strontiumL-diglutamate, containing two mono-hydrated glutamic acid moietiescomplexed to one strontium ion as a pentahydrate salt. The coordinatesfor the salt were identified as follows:

Strontium (L-) diglutamate pentahydrate was formed in uniform crystalsbelonging to the Monoclinic P2₁ space group with a unit size of a=8.7097Å, b=7.2450 Å and c=14.5854 Å, Volume: 904.891 (0.158) Å³. For detaileddescription of the X-ray crystallography procedure please see Example18.

The Strontium (L-) diglutamate pentahydrate crystal-composition isdepicted in FIGS. 3 and 4.

TABLE 4 Key interatomic distances (Å) for Strontium (L-) diglutamatepentahydrate crystals. Atomic numbering used are as depicted in FIG. 5.All H atom parameters were initially refined freely. In the final cyclesof Rietweld refinement, H atoms of CH₂ and CH groups were placed incalculated positions with C-H distances of 0.97 Å and 0.98 Årespectively and refined as riding atoms. For the water molecules in thecrystal structure, the O-H distances were restrained to 0.84 Å and theN-H distances were restained to 0.89 Å. The displacement parameters wereset to 1.2 (CH and NH) or 1.5 (OH) times U_(eq) of the corresponding C,N or O atoms. SR1-O11^((xi)) 2.603 (2) Sr1-O11^((xii)) 2.636 (2) Sr1-O52.605 (2) Sr1-O12^((xiii)) 2.639 (2) Sr1-O14 2.6130 (13) Sr1-O13 2.6478(12) Sr1-O6 2.619 (2) Sr1-O12^((xii)) 2.816 (2) Sr1-07 2.6326 (16)Symmetry codes: $^{({xi})}{{{- x} + 1},{{y - \frac{1}{2} - z + 1};}}$^((xii))x + 1, y, z;$^{({xiii})}{{{- x} + 1},{y + \frac{1}{2} - z + 1.}}$

TABLE 5 Hydrogen bond geometry (Å,°) of Strontium (L-) diglutamatepentahydrate. Atomic numbering used are as depicted in FIG. 5. D-H . . .A D-H H . . . A D . . . A D-H . . . A N11-H12 . . . O9^((x)) 0.89 (2)1.88 (2) 2.769 (3) 171 (3) N11-H13 . . . O7^((xi)) 0.87 (2) 2.19 (2)3.004 (3) 155 (2) N11-H14 . . . O23^((iii)) 0.88 (2) 1.87 (2) 2.715 (3)161 (2) N21-H22 . . . O24^((xiv)) 0.92 (2) 1.93 (2) 2.840 (3) 173 (3)N21-H23 . . . O23^((iii)) 0.88 (2) 1.96 (2) 2.805 (3) 162 (2) N21-H24 .. . O22^((xv)) 0.89 (2) 1.88 (2) 2.760 (3) 168 (2) O5-H1 . . .O13^((xvi)) 0.80 (2) 1.95 (2) 2.743 (3) 177 (4) O5-H2 . . . O21^((xvi))0.83 (2) 1.95 (2) 2.736 (3) 158 (3) O6-H3 . . . O13^((xvii)) 0.82 (2)1.89 (2) 2.698 (3) 173 (4) O6-H4 . . . O8^((xii)) 0.83 (2) 1.93 (2)2.738 (3) 167 (3) O7-H5 . . . O22^((xvi)) 0.81 (2) 1.96 (2) 2.763 (2)170 (3) O7-H6 . . . O24^((xiii)) 0.80 (2) 2.08 (2) 2.852 (2) 163 (3)O8-H7 . . . O14 0.81 (2) 1.91 (2) 2.722 (2) 178 (4) O8-H8 . . . O5^((x))0.83 (2) 2.11 (2) 2.866 (3) 150 (3) O9-H9 . . . O21 0.83 (2) 1.92 (2)2.745 (3) 176 (3) O9-H10 . . . O6^((xvi)) 0.81 (2) 1.99 (2) 2.765 (3)161 (3) Symmetry codes: $\;^{({iii})}x,{y + 1},{z;\begin{matrix}(x) & {{x - 1},y,{z;}}\end{matrix}}$ $^{({xi})}{{{- x} + 1},{{y - \frac{1}{2} - z + 1};}}$^((xii))x + 1, y, z;$^{({xiii})}{{{- x} + 1},{y + \frac{1}{2}},{{{- z} + 1};}}$$^{({xiv})}{{{- x} + 1},{y + \frac{1}{2}},{{{- z} + 2};}}$$^{({xv})}{{{- x} + 2},{y + \frac{1}{2}},{{{- z} + 2};}}$$^{({xvi})}{{{- x} + 2},{y + \frac{1}{2}},{{{- z} + 1};}}$$^{({xii})}{{{- x} + 2},{y - \frac{1}{2}},{{- z} + 1.}}$

TABLE 6 Torsion angles (°) of Strontium (L-) diglutamate pentahydrate.Atomic numbering used are as depicted in FIG. 5. (I) (II:1) (II:2)O1-C1-C2-C3 −107.3 (3) −109.8 (2) 91.3 (3) C1-C2-C3-C4 54.5 (3) 55.1 (3)70.7 (3) C2-C3-C4-C5 −178.5 (2) 177.4 (2) −179.6 (2) C3-C4-C5-O3 −56.3(4) −43.5 (4) −170.6 (2) O1-C1-C2-N1 17.5 (3) 128.3 (2) −28.3 (3)N1-C2-C3-C4 −73.0 (3) 176.8 (2) −169.4 (2)

Further improvements of the synthesis of strontium (L-) diglutamatepentahydrate may include degassing by nitrogen or by argon of the waterand of all aqueous solutions, which prevents contact to carbon dioxidethat eventually may lead to formation of impurities of strontiumcarbonate. It follows that a person skilled in the art will easily beable to adapt the procedure to proceed under an inert gas atmosphere.

Example 6 Preparation of Strontium Aspartate Trihydrate by Synthesis at100° C. According to the Invention

Initially, a suspension of aspartic acid (white colored) is prepared byadding 100 mL of millipore water to 13.311 g (0.1 moles) of solidL-aspartic acid (Fluka, C₅H₉NO₄, MW133.11 g/mole, CAS no. 56-84-8, lot.no. 432866/1, filling code 52603495) in a 250 mL beaker. To thissuspension was added 26.571 g (0.1 moles) of solid strontium hydroxide(Sigma Aldrich, Sr (OH)₂*8H₂O, MW 265.71, CAS no. 1311-10-0). Then, amagnetic stirring rod was added and the stirring and heating was startedto the point of boiling of the suspension. The final suspension is alsowhite colored and the stirring is sustained by maintaining a mediumrotation rate of the stirring apparatus. In order to prevent carbondioxide from entering the solution, the beaker was covered by a coveringglass.

After some minutes of boiling and stirring, the solution clarified andall the solid material dissolved. The boiling was maintained, andadditional water was added when required, as to replace the water lostby boiling. After three hours of boiling, the solution was filteredwhile boiling on a Büchner funnel. Very small amounts of impurities wereleft in the filter. The filtrate was subsequently allowed to cool toroom temperature, which resulted in growth of fine-powdered crystals ofstrontium aspartate trihydrate. Precipitation of the final productprogressed in the filtrate within an hour. The product was filtered anddried at 110° C. in an oven for ½ hour followed by drying 12 hours in adessicator over silica orange. Before analysis by x-ray crystallographyand by FAAS, the salts were ground by a mortar to fine powder.

The total yield of strontium aspartate trihydrate was approximately 98%before recrystallisation, and the majority of impurities consisted ofreminisces of the reagents and of strontium carbonate. This yield issignificantly higher than the yield obtained by synthesis underconventional conditions where only 3% was obtained (see Example 2). Thusthe high temperature synthesis method as disclosed herein provides asignificant gain in yield and a reduction in synthesis time, whileresulting in a strontium aspartate salt of higher purity. The productwas unambiguously identified as strontium aspartate trihydrate by x-raycrystallography and comparing the data to results of the CambridgeCrystallographic Database and information from H. Schmidbaur, P.Mikulcik & G. Müller (1990), Chem. Ber. 123; 1599-1602. For detaileddescription of the X-ray crystallography procedure see Example 18.

Further improvements of the synthesis may include degassing by nitrogenor by argon of the water and of all aqueous solutions, which preventscontact to carbon dioxide that eventually may lead to formation ofimpurities of strontium carbonate. It follows that a person skilled inthe art will easily be able to adapt the procedure to proceed under aninert gas atmosphere.

Example 7 Preparation of Strontium Malonate Anhydrate by Synthesis at100° C. According to the Invention

Initially, a suspension of malonic acid (white colored) is prepared byadding 100 mL of millipore water to 10.406 g (0.1 moles) of solidmalonic acid (Fluka, , MW 104.06 g/mole, CAS no. 141-82-2, lot. no.449503/1, filling code 44903076) in a 250 mL beaker. To this suspensionwas added 26.571 g (0.1 moles) of solid strontium hydroxide (SigmaAldrich, Sr (OH)₂*8H₂O, MW 265.71, CAS no. 1311-10-0). Then, a magneticstirring rod was added and the stirring and heating was started to thepoint of boiling of the suspension. The final suspension is also whitecolored and the stirring was sustained by maintaining a medium rotationrate of the stirring apparatus. In order to prevent carbon dioxide fromentering the solution, the beaker was covered by a covering glass.

After some minutes of boiling and stirring, the solution clarified andall the solid material dissolved. The boiling was maintained, andadditional water was added when required, as to replace the water lostby boiling. After three hours of boiling, the solution was filteredwhile boiling on a Büchner funnel. Very small amounts of impurities wereleft in the filter. The filtrate was subsequently allowed to cool toroom temperature, which resulted in growth of fine-powdered crystals ofstrontium malonate. Precipitation of the final product progressedrapidly during filtration and the majority of the product was found inthe filter (unheated). Only in rare instants, the precipitationprogressed in the filtrate. The product was filtered and dried at 110°C. in an oven for ½ hour followed by drying 12 hours in a dessicatorover silica orange. Before analysis by x-ray crystallography and byFAAS, the salts were ground by a mortar to fine powder.

The total yield of strontium malonate was approximately 98% beforerecrystallisation, and the majority of impurities consisted ofreminisces of the reagents and of strontium carbonate. The product wasunambiguously identified as strontium malonate (anhydrous) by x-raycrystallography and comparing the data to results of the CambridgeCrystallographic Database (please refer to description in Example 18).

In a further improvement of the synthesis, anhydrous strontium malonatewas produced in 10 kg scale in a method according to the presentinvention indicative of the applicability of the method for larger scalesynthesis. 15.80 kg Sr (OH)₂*8H₂O was dissolved in 63.21 purified waterand heated to 95-100° C. 5.63 kg malonic acid was dissolved in 4.11purified water, filtered where after an additional 1.41 of water wasadded and the solution heated to 95-100° C. The two solutions were mixedin a closed reaction vessel under an inert nitrogen atmosphere andstirred under reflux for 20 min. Subsequently the heating was stoppedand the solution was allowed to cool to 40-50° C. over 2-4 hours whilestrontium malonate was allowed to precipitate. The precipitate wasfiltered and the salt washed with an additional 13.21 of water, followedby drying to complete dryness at vacuum in a temperature of 70° C. 9.4kg anhydrous highly pure strontium malonate was obtained as a uniformmicrocrystalline white powder, corresponding to a yield of 94%. Theproduct was unambiguously identified as strontium malonate (anhydrous)by x-ray crystallography and comparing the data to results of theCambridge Crystallographic Database. For detailed description of theX-ray crystallography procedure please see Example 18.

Example 8 Methods of Manufacture of Strontium Salts of DicarboxylicAcids Using Temperatures Above 100° C. According to the Invention

According to methods developed previously and described in details inExamples 1 and 2, synthesis of strontium salts of dicarboxylic organicacids, and especially strontium salts of amino acids can be difficult toproduce in larger scale (i.e. >1 kg) due to low yields and difficultiesin separating the desired reaction products from contaminants. Strontiumsalts of carbonate are of special concern, as they will form asimpurities when the reaction is occurring in atmospheric air containingnormal levels of carbon dioxide. In Examples 4-7 the present inventorshave shown that the total yield of the product when strontium salts ofdicarboxylic acids are manufactured from the free acid form of the anionand strontium hydroxide, depends on temperature and on time ofsynthesis. In order for the reaction to reach completion, the mixture ofthe appropriate amino acid and strontium hydroxide needs boiling inwater, allowing ample time for strontium in the reaction mixture toreact with carbon dioxide in the air, if no other means or proceduresare employed to control the unwanted formation of strontium carbonate.In this example, the present inventors disclose methods of improving thesynthesis further by providing optimized reaction conditions, wheretemperature is increased above 100° C. in a closed container, and wherereaction times are significantly reduced, and where inert atmospheres ofcarbon-dioxide free gases easily can be introduced.

The present example provides representative data from the optimizationof conditions for synthesis of strontium L-glutamate hexahydrate in anautoclave system. In contrast to the conditions employed in Example 5,strontium hydroxide is used as starting material, which results in theformation of strontium L-glutamate hexahydrate. Strontium L-glutamate isused as an example, but the optimizations described in the example isalso applicable for the synthesis of other strontium salts, where theexact reaction conditions can be optimized as disclosed in this example.The reaction temperatures must be maintained below the melting point orbelow the temperature of decomposition of the organic anion moiety ofthe desired strontium salt.

Strontium L-glutamate was used as a model strontium compound in theoptimization experiments. The purity of the product was monitored bycomparing to crystallographic data and by measuring the content ofstrontium. Ideally, the content of strontium is 25.7% in strontiumL-glutamate hexahydrate, which is the product formed in theseexperiments. It follows that other strontium salts may be prepared bysimilar methods with high yield and purity.

Experimental

Preparation of Solutions: a Suspension of Glutamic Acid (White Coloured)is prepared by adding 100 mL of millipore water to 14.703 g (0.1 moles)of solid L-glutamic acid (Sigma Aldrich, C₅H₉NO₄, MW 187.14 g/mole, CASno. 142-47-2, lot. no. 426560/1, filling code 43003336) in a 250 mLbeaker. To this suspension was added 22.257 g, 26.571 g or 31.885 (0.08moles, 0.1 moles or 0.12 moles) of solid strontium hydroxide (SigmaAldrich, Sr (OH)₂*8H₂O, MW 265.71, CAS no. 1311-10-0).

Optimisation Experiments

After preparation of the salts, the nine optimizations experiments wereperformed according to the settings of Table 7. In this table, the term‘base-acid ratio’ indicates the molar ratio between strontium hydroxideand glutamic acid.

TABLE 7 Parameters and main results of the optimization procedure forsynthesis of strontium L-glutamate. The pressure was monitored but notused in the optimization process. The strontium content (% Sr) wasmeasured by FAAS but not used as quality parameter. The theoreticalstrontium content of strontium glutamate hexahydrate is 25.7%. The yield(%) was applied as the quality parameter. Autoclave Time of AutoclaveExperiment temperature synthesis Base-acid Total volume pressure % Srno. (° C.) (min.) ratio (ML) (bar) Yield % (AAS) 1 125 15 0.8 50 1.55 9425 2 124 30 1 75 1 112 22 3 124 60 1.2 100 1.6 121 21 4 127 15 1 100 1.2118 22 5 132 30 1.2 50 1.55 120 25 6 132 60 0.8 75 1.6 50 22 7 134 151.2 75 1.65 108 24 8 134 30 0.8 100 1.65 76 14 9 132 60 1 50 1.65 82 24Procedure

-   1. The calculated amount of acid was weighed and transferred to a    bluecap autoclave bottle and the Millipore water was added. The    bottle was closed and shaken, in order to obtain a finely grained    suspension.-   2. The calculated amount of strontium hydroxide octahydrate was    weighed and added to the acid solution of (1) and the bottle was    vigorously vortexed until all coarse lumps of material were    transformed into fine-grained powder.-   3. The bottle was placed in the autoclave and the temperature was    set. While in the autoclave no additional stirring was carried out.-   4. At t=100° C. the valve of the autoclave was closed and the timing    was started.-   5. During the autoclaving were monitored the actual temperature and    the actual pressure.-   6. After the time of autoclaving ended, the steam was let out, as    soon as possible, with due respect to safety precautions.-   7. At approx. 110° C. the autoclave was opened and the solution was    recovered. Again, the bottle was shaken, as to obtain a high degree    of mixing.-   8. The solution was immediately filtered hot on a Büchner funnel    after autoclaving, which left only traces of carbonate in the    filter. The product precipitated from the solution during cooling to    room temperature.-   9. After precipitation, the product was filtered and dried in an    oven for ½ an hour at 110° C. Then, it was dried in a dessicator    over silica-gel orange. Finally, the product was ground to fine    powder in a mortar.-   10. The product was weighed after grinding and the total yield    calculated.    Content of Strontium (% Sr):

A sample of 0.2 g was dissolved in 100 mL 0.1 M HNO₃ prepared inMillipore water. This solution was further diluted by a factor of 500 bya solution of 1% KCl, and the content of strontium was determined byFAAS. The measurements were performed by using a Perkin-Elmer 2100equipped with a hydrogen lamp for correction of the background signal.Strontium was measured at a slit width of 0.2 nm, the wavelength was460.8 nm operated at an energy of 58 and a current of 8 mA.

X-Ray Crystallography

A second check of purity was performed by powder x-ray crystallographyusing a Huber G670 diffractometer as described in more detail in Example18. A characteristic diffractogram of the strontium glutamate is shownin FIG. 5.

Results and Discussion

From the results listed in Table 7 above, it is apparent that some ofthe synthesis conditions resulted in relatively low yield and instrontium glutamate of low purity as apparent from the molar % ofstrontium in the reaction product. The product of experiment no. 8 wasproduced in relatively low yield, and it did not contain the expected25.7% of strontium. However, in general, the outcome of the optimizationexperiments is close to the expected products. Incomplete reactionprovides a product of too low content of strontium. Conditions employedin experiments 1 and 5 gave the strontium content in best agreement withthe expected value.

By studying the influence of the individual parameters on the totalyield (Table 4), it becomes clear that temperature, reaction time andbase-acid ratios are important for the synthesis while total volume isless important. A yield higher than 100%, which is observed inexperimental conditions 2, 3, 4, 5 and 7 (Table 7) originates fromincomplete drying, but this effect is almost eliminated when the averagevalues are considered.

The maximum yield was obtained by using a high temperature (133° C.), ashort reaction time and a surplus of strontium hydroxide. Accordingly,temperature is more important than time but it compares in importance tothe base-to-acid ratio. A 10^(th) experiment of control of optimizationwas performed, as to confirm the maximum yield of the optimizationexperiments, and the result of this experiment was in agreement with thefindings reported in Table 7.

Further improvements of the synthesis include introduction of inertatmospheres to the synthesis environment, as well as degassing of allsolutions by either nitrogen gas or by argon gas, as to reduce theformation of carbonate salts. Such salts may form readily in a normalair atmosphere and due to the very poor solubility of carbonate salts ofmost alkaline earth and alkali metals they will precipitate readily inthe reaction mixture.

Example 9 Methods of Manufacture of Strontium Malonate UsingTemperatures Above 100° C. According to the Invention

In order to confirm the applicability of the disclosed high temperaturesynthesis method for strontium salts other than strontium L-glutamate,strontium malonate was prepared by the high temperature synthesismethod. Basically the reaction conditions found for preparation ofstrontium L-glutamate (Example 8) was employed. A suspension of malonicacid (white coloured) is prepared by adding 100 mL of millipore water to10.41 g (0.1 moles) of solid malonic acid (FLUKA 63290, MW 104.1, CAS141-82-2) in a 250 mL beaker. To this suspension was added 22.257 g,26.571 g or 31.885 (0.08 moles, 0.1 moles or 0.12 moles) of solidstrontium hydroxide (Sigma Aldrich, Sr (OH)₂*8H₂O, MW 265.71, CAS no.1311-10-0). The reaction procedure described in Example 8 was followed,and the temperature was maintained below 130° C. to avoid decompositionof malonic acid, while the reaction time was maintained at 15 min.

Highest yield were obtained by the synthesis method using a molar ratioof Sr (OH)₂-to-acid of 1.2

An X-ray powder diffractogram of strontium malonate obtained by the hightemperature synthesis method disclosed in the present example is shownin FIG. 7. For detailed description of the X-ray crystallographyprocedure please see Example 18.

The revealed X-ray diffractogram of the synthesized malonate salt ofstrontium is in agreement with the previously described anhydrouscrystalline strontium malonate. It is apparent from the stable baseline,and well-defined spacing of diffraction peaks, that the crystal form ofthe malonate salt is homogeneous and pure. Thus crystalline pure andwell defined strontium malonate could easily be obtained by the hightemperature synthesis method.

Example 10 Preparation of a Novel Strontium Salt of D-Glutamic Acid bythe High Temperature Synthesis Method

An additional experiment was performed to validate the applicability ofthe high temperature synthesis method for the preparation of otherracemic strontium salts. Strontium D-glutamate was chosen. This salt hasnot been prepared previously. It was synthesized by preparing asuspension of D-glutamic acid as follows: 14.713 g (0.1 moles) of solidD-glutamic acid (Sigma-Aldrich HO₂CCH₂CH₂CH(NH₂)CO₂H, MW 147.13, CAS no.6893-26-1) was dissolved in 100 ml pure water in a 250 mL beaker. Tothis suspension was added 31.898 g (0.12 moles) of solid strontiumhydroxide (Sigma Aldrich, Sr (OH)₂*8H₂O, MW 265.71, CAS no. 1311-10-0).The reaction procedure described in example 8 was followed, and thetemperature was maintained a 132° C. and the reaction time wasmaintained at 15 min. After completion of the reaction, the strontiumD-glutamate salt was filtered, dried and subjected to X-ray diffractionanalysis to reveal the structure as described in example 18.

Strontium D-glutamate hexahydrate in was formed in uniform crystalsbelonging to the orthorhombic P2₁2₁2₁ space group with a unit size ofa=7.3244 Å, b=8.7417 Å and c=20.0952 Å, Volume: 1286.65 Å³. The crystalform of strontium D-glutamate hexahydrate was similar to the previouslydescribed structure of strontium L-glutamate hexahydrate (H. Schmidbaur,I. Bach, L. Wilkinson & G. Müller (1989), Chem. Ber. 122; 1433-1438).FIG. 8 depicts the structure and unit cell geometry of the crystals

The following coordinates were obtained (Table 8 and 9):

TABLE 8 Key interatomic distances for strontium D-glutamate withdistances in Angstrom. Sr1-O1^((i)) 2.623 (2) Sr1-O3^((iii)) 2.6639 (17)Sr1-O5 2.625 (2) Sr1-O2 2.6687 (18) Sr1-O2^((ii)) 2.635 (2) Sr1-O6 2.693(2) Sr1-O7 2.637 (2) Sr1-O1 2.7083 (19) Sr1-O4^((iii)) 2.6501 (17)Symmetry codes:$^{(i)}{{x - \frac{1}{2}},{{- y} + \frac{1}{2}},{{{- z} + 2};}}$$^{({ii})}{{x + \frac{1}{2}},{{- y} + \frac{1}{2}},{{{- z} + 2};}}$^((iii))x, y + 1, z.

TABLE 9 Coordinates of strontium D-glutamate. Coordinates of hydrogenatoms are included in the table, and the atom numbering are as shown inFIG. 5. D-H . . . A D-H H . . . A D . . . A D-H . . . A N1-H3 . . .O4^((iv)) 0.90 (2) 2.40 (2) 3.283 (3) 169 (3) O5-H8 . . . O9^((v)) 0.84(2) 1.95 (2) 2.768 (3) 163 (3) O5-H9 . . . O10^((vi)) 0.81 (2) 2.14 (2)2.939 (3) 168 (3) O6-H10 . . . O8^((v)) 0.80 (2) 1.97 (2) 2.740 (3) 160(4) O6-H11 . . . O3^((viii)) 0.78 (2) 2.01 (2) 2.783 (3) 170 (4) O7-H12. . . O3^((iv)) 0.81 (2) 1.90 (2) 2.713 (3) 177 (3) O7-H13 . . .O8^((v)) 0.83 (2) 1.90 (2) 2.719 (3) 170 (3) O8-H14 . . . O10^((viii))0.78 (2) 1.94 (2) 2.711 (3) 171 (3) O8-H15 . . . O4^((v)) 0.80 (2) 1.91(2) 2.708 (3) 176 (4) O9-H16 . . . O7^((v)) 0.80 (2) 2.00 (2) 2.766 (3)163 (3) O9-H17 . . . N1^((ix)) 0.81 (2) 1.93 (2) 2.735 (3) 176 (3)O10-H18 . . . O9^((x)) 0.81 (2) 1.97 (2) 2.775 (3) 172 (4) O10-H19 . . .O6^((v)) 0.80 (2) 2.00 (2) 2.796 (3) 178 (4) Symmetry codes:$^{({iv})}{{x + \frac{1}{2}},{{- y} - \frac{1}{2}},{{{- z} + 2};}}$^((v))x, y, z;$^{({vi})}{{{- x} + 1},{y + \frac{1}{2}},{{- z} + \frac{3}{2}}}$$^{({vii})}{{x - \frac{1}{2}},{{- y} - \frac{1}{2}},{{{- z} + 2};}}$$^{({viii})}{{{- x} + 1},{y - \frac{1}{2}},{{{- z} + \frac{1}{2}};}}$$^{({ix})}{{{- x} + \frac{1}{2}},{- y},{{z - \frac{1}{2}};}}$^((x))x − 1, y, z.

Example 11 Synthesis of Strontium Formate

Basically the reaction conditions found for preparation of strontiumL-glutamate (example 8) was employed. A suspension of malonic acid(white coloured) is prepared by adding 100 mL of millipore water to4.603 g (0.1 moles) of solid formic acid (FLUKA 33015, MW 104.1, CAS64-18-6) in a 250 mL beaker. To this suspension was added 31.898 g (0.12moles) of solid strontium hydroxide (Sigma Aldrich, Sr (OH)₂*8H₂O, MW265.71, CAS no. 1311-10-0). The reaction procedure described in Example8 was followed.

Example 12 Synthesis of Magnesium Malonate

Magnesium malonate in pure form was synthesized in high yield and purityusing the reaction conditions found for preparation of strontiummalonate (example 9). A suspension of sodium malonate (white colored) isprepared by adding 100 mL of millipore water to 16.605 g (0.1 moles) ofsolid sodium malonate dibasic monohydrate (SIGMA M1875-100 G, MW 166.05,CAS 26522-85-0) in a 250 mL beaker. To this suspension was added 24.410g (0.12 moles) of solid magnesium chloride hexahydrate (FLUKA 63068,MgCl₂*6H₂O, MW 203.3, CAS 7791-18-6). The reaction procedure describedin Example 8 was followed.

Example 13 Synthesis of Zinc L-Glutamate Dihydrate

Basically the reaction conditions found for preparation of strontiumL-glutamate (Example 8) was employed. A suspension of sodium glutamate(white coloured) is prepared by adding 100 mL of millipore water to18.714 g (0.1 moles) of solid L-glutamic acid monosodium saltmonohydrate (ALDRICH G2834, MW 187.14, CAS 142-47-2) in a 250 mL beaker.To this suspension was added 13.628 g (0.1 moles) of solid zinc chloride(FLUKA, 96469, MW 136.28, CAS 7646-85-7). The reactants were placed inthe sealed container in an autoclave, and temperature was increased to132° C. for 15 min whereafter the reaction was stopped and after thereaction mixture reached a temperature of 92-98° C., it was filtered ona Büchner funnel, and the desired zinc L-glutamate salt readilyprecipitated from the filtrate. The yield was approximately 95% andpurity higher than 96%.

Example 14 Synthesis of Zinc Malonate Dihydrate

Basically the reaction conditions found for preparation of zincL-glutamate (Example 13) was employed. A suspension of sodium malonate(white coloured) is prepared by adding 100 mL of millipore water to16.605 g (0.1 moles) of solid sodium malonate dibasic monohydrate (SIGMAM1875-100G, MW 166.05, CAS 26522-85-0) in a 250 mL beaker. To thissuspension was added 13.628 g (0.1 moles) of solid zinc chloride (FLUKA,96469, MW 136.3, CAS 7646-85-7). Subsequent manufacturing steps were asdescribed in Example 13.

Example 15 Synthesis of Barium L-Glutamate

Basically the reaction conditions found for preparation of strontiumL-glutamate (Example 8) was employed. A suspension of L-glutamic acid(white coloured) is prepared by adding 100 mL of millipore water to14.713 g (0.1 moles) of solid L-glutamic acid (FLUKA 49449, MW 147.13,CAS 56-86-0) in a 250 mL beaker. To this suspension was added 37.86 g(0.12 moles) of solid barium hydroxide octa hydrate (FLUKA 11780, Ba(OH)₂*8H₂O, MW 315.5, CAS 12230-71-6). The reaction procedure describedin Example 8 was followed.

Example 16 Synthesis of Calcium L-Glutamate

Basically the reaction conditions found for preparation of strontiumL-glutamate (Example 8) was employed. A suspension of sodium glutamate(white coloured) is prepared by adding 100 mL of millipore water to18.714 g (0.1 moles) of solid L-glutamic acid monosodium saltmonohydrate (ALDRICH G2834, MW 187.14, CAS 142-47-2) in a 250 mL beaker.To this suspension was added 17.6424 g (0.12 moles) of solid calciumchloride dihydrate (FLUKA, 21097, MW 147.0, CAS 10035-04-8). Thereaction procedure described in Example 8 was followed.

Example 17 Synthesis of Calcium Malonate

Basically the reaction conditions found for preparation of strontiummalonate (example 9) was employed. A suspension of sodium malonate(white coloured) is prepared by adding 100 mL of millipore water to16.605 g (0.1 moles) of solid sodium malonate dibasic monohydrate (SIGMAM1875-100 G, MW 166.05) in a 250 mL beaker. To this suspension was added17.6424 g (0.12 moles) of solid calcium chloride dihydrate (FLUKA,21097, MW 147.0, CAS 10035-04-8). The reaction procedure described inExample 8 was followed.

Example 18 Determination of Crystal Structure by X-Ray Diffraction

General

The inventors define a crystalline material as having a structure with athree-dimensional repetition, i.e. there is a smallest identical unit,the unit cell, which by translations in three dimensions will fit to anypart of the crystal. The unit cell dimensions are typically between 3and 25 Å for inorganic and organic materials. Such a three-dimensionalarray of unit cells will also contain sets of lattice planes connectingall corners of the unit cells. The distance between the lattice planesin such a set will be from zero up to the maximum dimension of the unitcell itself. The plane distances are thus in the same order of magnitudeas the X-ray wavelength used for diffraction, 0.5-2.4 Å. When such acrystal is placed in an X-ray beam it will act as a grating to create acharacteristic interference or diffraction pattern. The positions of therecorded diffracted radiation will be determined by the lattice planedistances, i.e. the size of the unit cell, while the recorded diffractedintensities are determined by the positions and symmetry of the atoms inthe unit cell. For practical purposes it means that a unique crystalstructure will produce a unique diffraction pattern that can be used foridentification or to determine the crystal structure. There are twogeneral methods commonly used for structure analysis: The single-crystalmethod and the powder diffraction method.

Single-Crystal Methods

This method is primarily used to determine the crystal structures ofunknown materials. As the name implies just one crystal, typically lessthan 0.3 mm in size, is used. The crystal is mounted on a single-crystaldiffractometer where it can be rotated in independent directions and acomplete three-dimensional diffraction pattern can be collected in aboutten hours. From the positions of the diffraction spots the unit celldimensions may be calculated and from the intensity of the spots theatomic arrangement within the unit cell may be solved. The solvedstructure is unique within the accuracy, typically better than 0.01 Å ininteratomic distances and the method is also sensitive to the absoluteconfirmation of the molecules in the structure. With moderndiffractometers and software the method is successful to 99% withorganic and metal organic compounds.

Powder Diffraction

A powder sample will ideally contain an infinite amount of micrometersized crystals in random orientation. When radiated by X-ray each of thecrystallites will diffract independently and add its contribution to thediffraction pattern. As a result a powder diffraction pattern will be aone-dimensional projection of the three-dimensional single-crystalpattern. The interpretation of a powder diffraction pattern is much lessstraightforward than a single-crystal pattern. Depending on unit cellsize and symmetry a powder diffraction pattern show various degrees ofreflection overlap. Nevertheless, the peak positions are still afunction of the unit cell dimensions and the intensities a function ofthe unit cell contents. A powder diffraction pattern is more or less afingerprint of the investigated structure, and using a powderdiffraction data base and an effective search-match program the presentinventors can with 10 minutes of data collection and a few minutesanalysis safely identify known structures. Powder diffraction has becomethe workhorse for structural characterization of materials in general.Except for phase identification, the method is commonly used forstructure solution, structure refinements and for studies ofcrystallinity, crystallite size and size distributions, stress/strainetc. Although the method is primarily intended for solid crystallinematerials, information from amorphous and fibrous materials and thinfilms is also readily obtained.

Powder diffraction equipment Diffracto- Huber G670 powder diffractometeroperating in Guinier meter: (transmission) geometry and equipped with aprimary quartz focusing monochromator and an imaging plate detector withan integrated laser/photomultiplier read-out system X-ray 40 kV and 30mA. generator: Radiation: CuKα1 1.54059 Å Instrument Intensity and2θ-scale checked with a Si-standard calibration: (NBS) fitted throughfull pattern Rietveld refine- ments. Calibrated approximately once aweek and after any adjustment of the diffractometer. Sample holder: Flatplate scotch tape, 10 by 10 mm active area in Scotch tape Measurement:Range: 2 to 100° in 2θ. Detector is read out in steps of 0.05° in 2θ.Exposure time is between 15 and 120 min depending on scattering power.Measurement The samples are ground by an agate mortar and pestleprocedure: and put on the sample holder on the Scotch tape. The sampleholder is mounted on the powder diffractometer mount and the rockingmotor is started. In the data collection program the file name is given(typically the sample name) and any other comments or observations areentered. The measuring time is entered and the data collection started.The file name, measuring time and operator is written in the note book.After completed measurement the powder diffraction pattern is printedand signed by the operator. An attempt to identify the sample using thesearch-match program will usually be made.

REFERENCES

-   Briggman B & Oskasson Å 1977, Acta Cryst. B33; 1900-1906-   Schmidbaur H et al. Chem. Ber. (1989) 122: 1433-1438-   Schmidbaur, H, P. Mikulcik & G. Müller (1990), Chem. Ber. 123;    1599-1602

1. A method for the preparation of a strontium salt of an organicdicarboxylic acid, the method comprising reacting at least one of ahydroxide and/or a halogen inorganic salt of strontium with the organicdicarboxylic acid in an aqueous medium at a temperature of about 90° C.or more for a time period of at the most about 60 minutes in a reactionmixture, and wherein the molar ratio between the hydroxide and/or thehalogen inorganic salt of strontium and the organic dicarboxylic acid isin the range from 1:1 to 1.2:1.
 2. The method according to claim 1,wherein the molar ratio between the hydroxide and/or the halogeninorganic salt of strontium and the organic dicarboxylic acid is in therange from 1.05:1 to 1.2:1.
 3. The method according to claim 1, whereinthe molar ratio between the hydroxide and/or the halogen inorganic saltof strontium and the organic dicarboxylic acid is in the range from1.1:1 to 1.2:1.
 4. The method according to claim 1, wherein the molarratio between the hydroxide and/or the halogen inorganic salt ofstrontium and the organic dicarboxylic acid is 1:1.
 5. The methodaccording to claim 1, wherein the organic dicarboxylic acid is selectedfrom the group consisting of: fumaric acid, maleic acid, malonic acid,tartaric acid, oxalic acid, L- and D-glutamic acid, L- and D-asparticacid, acetonedicarboxylic acid, adipic acid, alpha-ketoglutaric acid,azelaic acid, citraconic acid, cyclopentane-1,2-dicarboxylic acid,cystathionine, glutaconic acid, glutaric acid, itaconic acid,lanthionine, malic acid, mesaconic acid, pimelic acid, sebacic acid,suberic acid, succinic acid, and terephthalic acid.
 6. The methodaccording to claim 1, wherein the organic dicarboxylic acid is an aminocarboxylic acid.
 7. The method according to claim 1, wherein thestrontium salt of the organic dicarboxylic acid is selected from thegroup consisting of strontium glutamate, strontium aspartate, strontiummalonate, strontium D-glutamate, strontium L-glutamate, strontium (L-)diglutamate pentahydrate, strontium D-aspartate, strontium L-aspartate,strontium maleate, strontium fumarate and strontium succinate.
 8. Themethod according to claim 7, wherein the strontium salt of the organicdicarboxylic acid is strontium malonate.
 9. The method according toclaim 1, wherein the at least one of a hydroxide and/or a halogeninorganic salt of strontium is the halogen inorganic salt of thestrontium.
 10. The method according to claim 9, wherein the halogeninorganic salt of strontium is a chloride salt.
 11. The method accordingto claim 1, where the reaction is performed in a closed container at atemperature of 100° C. or more and a pressure of 1 bar or more.
 12. Themethod according to claim 2 comprising reacting strontium hydroxide withthe organic dicarboxylic acid at a temperature in a range of from about120° C. to about 135° C. and at a pressure of from about 1 to about 1.7bar for a time period of from about 15 minutes to about 60 minutes toobtain the strontium salt of the organic dicarboxylic acid.
 13. Themethod according to claim 1 further comprising isolating the strontiumsalt of the organic dicarboxylic acid by precipitating the strontiumsalt from the reaction mixture by adding 5-60 vol/vol % alcohol to thereaction mixture.
 14. The method according to claim 13, where thealcohol is ethanol.
 15. The method according to claim 13, where thealcohol is methanol.
 16. The method according to claim 1, wherein thetemperature is about 100° C. or more.
 17. The method according to claim1, wherein the temperature is about 120° C. or more.
 18. The methodaccording to claim 1, wherein the temperature is about 125° C. or more.19. The method according to claim 1, wherein the time period is at themost about 30 minutes.
 20. The method according to claim 1, wherein thetime period is at the most about 20 minutes.
 21. The method according toclaim 1, wherein the time period is about 15 minutes.
 22. The methodaccording to claim 6, wherein the amino carboxylic acid is a naturalamino acid.
 23. The method according to claim 6, wherein the aminocarboxylic acid is a synthetic amino acid.
 24. The method according toclaim 13 wherein 5-40 vol/vol % alcohol is added to the reactionmixture.
 25. The method according to claim 13 wherein 10-25 vol/vol %alcohol is added to the reaction mixture.
 26. The method according toclaim 1, wherein said reacting is conducted under an inert gas or steamatmosphere.